Lili Fu

Efficacy of short-term high-dose statin in preventing contrast-induced nephropathy: a meta-analysis of seven randomized controlled trials.

Background A few studies focused on statin therapy as specific prophylactic measures of contrast-induced nephropathy have been published with conflicting results. In this meta-analysis of randomized controlled trials, we aimed to assess the effectiveness of shor-term high-dose statin treatment for the prevention of CIN and clinical outcomes and re-evaluate of the potential benefits of statin therapy. Methods We searched PubMed, OVID, EMBASE, Web of science and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials comparing short-term high-dose statin treatment versus low-dose statin treatment or placebo for preventing CIN. Our outcome measures were the risk of CIN within 2–5 days after contrast administration and need for dialysis. Results Seven randomized controlled trials with a total of 1,399 patients were identified and analyzed. The overall results based on fixed-effect model showed that the use of short-term high-dose statin treatment was associated with a significant reduction in risk of CIN (RR = 0.51, 95% CI 0.34–0.76, p = 0.001; I2 = 0%). The incidence of acute renal failure requiring dialysis was not significant different after the use of statin (RR = 0.33, 95% CI 0.05–2.10, p = 0.24; I2 = 0%). The use of statin was not associated with a significant decrease in the plasma C-reactive protein level (SMD −0.64, 95% CI: −1.57 to 0.29, P = 0.18, I2 = 97%). Conclusions Although this meta-analysis supports the use of statin to reduce the incidence of CIN, it must be considered in the context of variable patient demographics. Only a limited recommendation can be made in favour of the use of statin based on current data. Considering the limitations of included studies, a large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for statin in CIN prevention.

VEGF-modified human embryonic mesenchymal stem cell implantation enhances protection against cisplatin-induced acute kidney injury

The implantation of mesenchymal stem cells (MSC) has been reported as a new technique to restore renal tubular structure and improve renal function in acute kidney injury (AKI). Vascular endothelial growth factor (VEGF) plays an important role in the renoprotective function of MSC. Whether upregulation of VEGF by a combination of MSC and VEGF gene transfer could enhance the protective effect of MSC in AKI is not clear. We investigated the effects of VEGF-modified human embryonic MSC (VEGF-hMSC) in healing cisplatin-injured renal tubular epithelial cells (TCMK-1) with a coculture system. We found that TCMK-1 viability declined 3 days after cisplatin pretreatment and that coculture with VEGF-hMSC enhanced cell protection via mitogenic and antiapoptotic actions. In addition, administration of VEGF-hMSC in a nude mouse model of cisplatin-induced kidney injury offered better protective effects on renal function, tubular structure, and survival as represented by increased cell proliferation, decreased cellular apoptosis, and improved peritubular capillary density. These data suggest that VEGF-modified hMSC implantation could provide advanced benefits in the protection against AKI by increasing antiapoptosis effects and improving microcirculation and cell proliferation.

The nephroprotective effect of tauroursodeoxycholic acid on ischaemia/reperfusion-induced acute kidney injury by inhibiting endoplasmic reticulum stress.

The incidence of acute kidney injury (AKI) is very high, and multiple physiopathological processes are involved, including endoplasmic reticulum stress (ERS). Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid derivative that has been reported to inhibit ERS. To determine whether TUDCA had a nephroprotective effect on AKI and to explore the exact mechanism, an ischaemia/reperfusion (I/R)‐induced AKI mouse model and a tunicamycin‐pre‐treated TCMK‐1 cell model were established. It was found that the renal tubular necrosis score and cell apoptosis index reached their peak 24 hr after I/R. GRP78 and C/EBP homologous protein (CHOP) expression and Caspase 12 activation were enhanced, reaching their peaks at 4 and 12 hr, respectively. TUDCA intervention not only decreased the renal tubular necrosis score and the cell apoptosis index but also down‐regulated GRP78 and CHOP expression and Caspase 12 activation. The survival rate of TCMK‐1 cells pre‐treated with TUDCA was significantly higher than that of TCMK‐1 cells without TUDCA pre‐treatment. In conclusion, TUDCA had a nephroprotective effect on IR‐induced AKI by inhibiting ERS and by blocking GRP78 and CHOP expression, reducing Caspase 12 activation and inhibiting cell apoptosis.

Effect of Theophylline on Prevention of Contrast-Induced Acute Kidney Injury: A Meta-analysis of Randomized Controlled Trials

BACKGROUND Whether treatment with adenosine receptor antagonists such as theophylline can prevent contrast-induced acute kidney injury (AKI) remains controversial. STUDY DESIGN We conducted a meta-analysis of randomized controlled trials using MEDLINE (1966 to July 2011), EMBASE (1980 to July 2011), Web of Science (1986 to July 2011), and the Cochrane Central Register of Controlled Trials (1996 to July 2011), without language restriction. SETTING & POPULATION Patients undergoing contrast procedures. SELECTION CRITERIA FOR STUDIES Randomized controlled trials assessing adenosine antagonists versus control for prevention of contrast-induced AKI. INTERVENTION Adenosine antagonists with or without N-acetylcysteine versus control with or without N-acetylcysteine. OUTCOMES Contrast-induced AKI, change in serum creatinine level, requirement of dialysis, and in-hospital mortality. RESULTS 16 trials (1,412 participants) were included. Theophylline significantly decreased the risk of contrast-induced AKI (13 trials, 1,222 patients; risk ratio, 0.48; 95% CI, 0.26-0.89; P = 0.02; I(2) = 45%) and had a protective effect on the absolute change in serum creatinine concentration (13 trials, 1,170 patients; standardized mean difference, -0.31 mg/dL; 95% CI, -0.50 to -0.11; P = 0.002; I(2) = 60%). Meta-regression showed a significant relation between the relative risk of contrast nephropathy and baseline serum creatinine level or Jadad score. No clear effects of treatment on risk of dialysis and in-hospital mortality were identified. LIMITATIONS Power to assess clinical end points was limited. CONCLUSIONS Theophylline treatment significantly reduced the incidence of contrast-induced AKI and had a modest improvement on kidney function after contrast exposure in the general population. However, beneficial effects of theophylline were not observed in patients with high baseline creatinine values (serum creatinine ≥1.5 mg/dL). In addition, the long-term effect of this agent on more clinically important outcomes was not established. Future large-scale high-quality multicenter trials in participants with different underlying risks of contrast-induced AKI and that incorporate the evaluation of clinically relevant outcomes are required.

Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats: a role for KLF15

Dietary protein restriction is an important treatment for chronic kidney disease. Herein, we tested the effect of low-protein or low-protein plus ketoacids (KA) diet in a remnant kidney model. Rats with a remnant kidney were randomized to receive normal protein diet (22%), low-protein (6%) diet (LPD), or low-protein (5%) plus KA (1%) diet for 6 months. Protein restriction prevented proteinuria, decreased blood urea nitrogen levels, and renal lesions; however, the LPD retarded growth and decreased serum albumin levels. Supplementation with KA corrected these abnormalities and provided superior renal protection compared with protein restriction alone. The levels of Kruppel-like factor-15 (KLF15), a transcription factor shown to reduce cardiac fibrosis, were decreased in remnant kidneys. Protein restriction, which increased KLF15 levels in the normal kidney, partially recovered the levels of KLF15 in remnant kidney. The expression of KLF15 in mesangial cells was repressed by oxidative stress, transforming growth factor-β, and tumor necrosis factor (TNF)-α. The suppressive effect of TNF-α on KLF15 expression was mediated by TNF receptor-1 and nuclear factor-κB. Overexpression of KLF15 in mesangial and HEK293 cells significantly decreased fibronectin and type IV collagen mRNA levels. Furthermore, KLF15 knockout mice developed glomerulosclerosis following uninephrectomy. Thus, KLF15 may be an antifibrotic factor in the kidney, and its decreased expression may contribute to the progression of kidney disease.

Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats

Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.

Oxidized high-density lipoprotein enhances inflammatory activity in rat mesangial cells.

Inflammation is a mechanism of glomerular damage in chronic glomerulopathies, in which dyslipidaemia plays an important role. Unlike native high‐density lipoprotein (HDL), oxidized HDL is thought to be an adverse factor in chronic ischaemic disease and may increase the production of inflammatory cytokines in atheromatous plaques and plasma, but the effect of oxidized HDL on mesangial cells remains unclear.

Design, synthesis and antitumor evaluation of a new series of N-substituted-thiourea derivatives

AbstractAim:To design and synthesize a novel class of protein tyrosine kinase inhibitors, featuring the N-(2-oxo-1,2-dihydroquinolin-3-yl-methyl)-thiourea framework.Methods:First, compounds 1 and 2 were identified using the virtual screening approach in conjunction with binding assay based on surface plasmon resonance. Subsequently, 3 regions of compounds 1 and 2 were selected for chemical modification. All compounds were characterized potent inhibitory activities toward the human lung adenocarcinoma cell line SPAC1.Results:Forty new compounds (1–2, 3a–g, 4a–w, and 5a–l) were designed, synthesized and bioassayed. Six compounds (1, 3e, 4l, 4w, 5a, and 5b) were found to show promising inhibitory activity against the SPAC1 tumor cell line. The inhibitory activity of compound 5a increases approximately 10 times more than that of the original compound 1.Conclusion:This study provides a promising new template with potential antitumor activity.

Kruppel-Like Factor 15 Modulates Renal Interstitial Fibrosis by ERK/MAPK and JNK/MAPK Pathways Regulation

Background/Aims: Renal interstitial fibrosis is a hallmark of progressive chronic kidney disease (CKD). Previous studies reported that kruppel-like factor 15 (KLF15) is an important regulator of cardiac fibrosis and could reduce the expression of extracellular matrix in mesangial cells. However, the role of this transcription factor in renal interstitial fibrosis has not been reported. Methods: In this study, we examined KLF15 expression in the remnant kidney of 5/6 nephrectomized rats 12 or 24 weeks after operation. In vitro we examined the effect of altered KLF15 expression on the production of extracellular matrix and the pro-fibrotic factor CTGF in rat renal fibroblasts (NRK-49F), and further explored the related mechanisms. Results: The level of KLF15 was drastically decreased in the renal interstitium of 5/6 nephrectomized rats with progressive interstitial fibrosis, especially at 24 weeks. Our in vitro evidence showed that overexpression of KLF15 repressed basal and transforming growth factor-β1 (TGF-β1)-induced extracellular matrix and CTGF in NRK-49F cells. In addition, TGF-β1-mediated activation of extracellular-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (JNK) /MAPK downregulated KLF15 expression and increased the level of extracellular matrix and CTGF, and all these effects were completely abolished by ERK1/2 inhibitor and JNK inhibitor in NRK-49F cells. Conclusions: Our findings implicate that KLF15 plays an important role and may prove to be an antifibrotic factor in renal interstitial fibrosis through regulation of ERK/MAPK and JNK/MAPK signaling pathways.

Rosiglitazone inhibits transforming growth factor-β1 mediated fibrogenesis in ADPKD cyst-lining epithelial cells.

Background Interstitial fibrosis plays an important role in progressive renal dysfunction in autosomal dominant polycystic kidney disease (ADPKD). In our previous studies, we confirmed that PPAR-γ agonist, rosiglitazone could protect renal function and prolong the survival of a slowly progressive ADPKD animal model by reducing renal fibrosis. However, the mechanism remains unknown. Methods Primary culture epithelial cells pretreated with TGF-β1 were incubated with rosiglitazone. Extracellular matrix proteins were detected using real-time PCR and Western blotting. MAPK and Smad2 phosphorylation were measured with western blot. ERK1/2 pathway and P38 pathway were inhibited with the specific inhibitors PD98059 and SB203580. The Smad2 pathway was blocked with the siRNA. To address whether PPAR-γ agonist-mediated inhibition of TGF-β1–induced collagen type I expression was mediated through a PPAR-γ dependent mechanism, genetic and pharmaceutical approaches were used to block the activity of endogenous PPARγ. Results TGF-β1-stimulated collagen type I and fibronectin expression of ADPKD cyst-lining epithelia were inhibited by rosiglitazone in a dosage-dependent manner. Smad2, ERK1/2 and P38 pathways were activated in response to TGF-β1; however, TGF-β1 had little effect on JNK pathway. Rosiglitazone suppressed TGF-β1 induced Smad2 activation, while ERK1/2 and P38MAPK signals remained unaffected. Rosiglitazone could also attenuate TGF-β1-stimulated collagen type I and fibronectin expression in primary renal tubular epithelial cells, but had no effect on TGF-β1–induced activation of Smad2, ERK1/2 and P38 pathways. There was no crosstalk between the Smad2 and MAPK pathways in ADPKD cyst-lining epithelial cells. These inhibitory effects of rosiglitazone were reversed by the PPARγ specific antagonist GW9662 and PPARγ siRNA. Conclusion ADPKD cyst-lining epithelial cells participate in TGF-β1 mediated fibrogenesis. Rosiglitazone could suppress TGF-β1–induced collagen type I and fibronectin expression in ADPKD cyst-lining epithelia through modulation of the Smad2 pathway. Our study may provide therapeutic basis for clinical applications of rosiglitazone in retarding the progression of ADPKD.